Despite frequent initial responses to platinum/taxane therapy after surgical debulking, most patients with advanced epithelial ovarian cancer (EOC) develop drug resistance that leads to low responsiveness to any agent and shortened survival. Thus, devising new and innovative therapeutic strategies is a critical need to combat drug resistant ovarian cancer. In the current proposal, we propose to utilize gold nanoparticle (GNP) as a unique tool to disrupt multicellular crosstalk responsible for drug resistance and devise new and innovative therapeutic strategies to improve dismal prognosis in advanced epithelial ovarian cancer. The importance of angiogenesis in recurrent EOC is underscored by the ICON-6 trial that for the first time demonstrated a significant improvement both in the progression free survival (PFS) and overall survival (OS) using cediranib, a potent oral inhibitor of all three VEGF receptor tyrosine kinases. Also crosstalk between endothelial cell (ECs) and ovarian cancer stem-like cells (OCSCs) has been implicated in drug resistance. In separate studies, abundance of cancer-associated fibroblasts (CAFs) was correlated with advanced stage of the disease and poor prognosis in EOCs. Although the molecular mechanisms are far from clear, a number of GFs and cytokines such as hepatocyte growth factor (HGF), stromal derived factor-1 (SDF- 1), fibroblast growth factor (FGF), transforming growth factor (TGF), are recognized to play critical roles in the pathogenesis of EOCs. Based on these results we hypothesize that a triangular crosstalk among cancer cells (CCs), CAFs and ECs are critical for tumor growth, metastasis and drug resistance in EOC (Scheme 1). In this context, exploiting self-therapeutic property of GNPs to disrupt the triangular crosstalk and identifying key molecules responsible for drug resistance is a highly innovative approach that will drive the design of new therapeutic strategies to treat recurrent, drug resistant EOC. Successful completion of the aims proposed will help to understand the molecular mechanism of desmoplasia, provide a new and innovative way to inhibit it, and device new therapeutic strategies to enhance drug sensitivity that will inhiit tumor growth, metastasis and improve prognosis in PDAC where practically no effective therapy is currently available. We will test the hypothesis using following specific aims; Aim 1: Investigate a role of triangular crosstalk in EOC pathogenesis and its interrogation by GNP; Aim 2: Identify key molecular machineries and pathways responsible for triangular crosstalk using GNP; Aim 3: Interrogating triangular crosstalk in vivo and overcoming therapy resistance by GNP. Results from the present application will determine roles of multicellular crosstalk in the evolution of drug resistance phenotype, identify key molecules responsible for it, provide novel and unique therapeutic strategies to overcome therapy resistance, and pave way for translatable therapy for drug resistant ovarian cancer patients where no effective therapy is currently available.